Otitis media (OM) is the most common disease for which children receive medical care in the United States. Complications and sequelae of OM contribute significantly to pediatric morbidity and impose a large economic burden on society. This proposal is a revised, competing renewal application requesting an additional 3 years of support for an existing program project with the unifying concept of basic and clinical studies in OM and a primary theme of OM pathogenesis. The program includes three ongoing projects, and two supporting core units (administration and biostatistics). Project 1, "A Prospective Twin Study of Otitis Media" is an ongoing study designed to determine the contribution of genetics to OM pathogenesis. The requested funding is needed to complete the follow-up of currently enrolled twin pairs and analyze the data to test the hypothesis that susceptibility to OM has a genetic component. If a significant genetic contribution is documented, provisions have been made that allow for the application of bimolecular technologies to these twin pairs for purposes of identifying the genetic basis for the predisposition. The results will be used to identify "at risk" children for close monitoring and early intervention. Project 2, "Middle Ear Pathophysiology", is a continuation of a current study designed to develop and test mathematical models of middle ear pressure regulation. Funds are requested to perform experiments that validate current models of pressure regulation with a specific focus on the effects of an inflamed middle ear mucosa. These data will be used to: define the role of dysregulation in the pathogenesis of OM; develop diagnostic tests of dysregulation for use in children, and suggest rational, alternative interventions to prevent or treat OM. Project 3, "Modulation of Cytokine Expression in Otitis Media with Effusion" is a direct extension of an ongoing study, "Biochemical Studies of Otitis Media" and uses pharmacological probes to dissect the role of host produced, proinflammatory, biological chemicals in initiating and sustaining OM pathogenesis. This knowledge is fundamental to understanding the control of the inflammatory process in OM and holds significant promise for identifying rational treatments. These three projects are mutually supportive, complement existing and planned studies of OM conducted by investigators at our institution and bring closure to those areas of investigation identified in the objectives of the program project as originally presented. It is anticipated that the results of these studies will be of direct and consequential benefit to the many infants and children suffering from OM.